Neuroscience
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Recently, we have reported that 6R-tetrahydrobiopterin activates Ca2+ channels in neuronal cells independently of its cofactor activities. Several reports indicate that depolarization-induced activation of Ca2+ channels enhances neuronal survival. Here, we investigated the effects of 6R-tetrahydrobiopterin on survival of differentiated PC12 cells. ⋯ The effect of 6R-tetrahydrobiopterin was mimicked by a cyclic-AMP analogue and inhibited by an inhibitor for protein kinase A. Ca2+ channel activity was preserved but dopamine-releasing activity was disturbed in surviving cells cultured with 6R-tetrahydrobiopterin. 6R-Tetrahydrobiopterin had no effect on mitogen-activated protein kinase. These findings suggest that, independently of its cofactor activities and mitogen-activated protein kinase cascade, 6R-tetrahydrobiopterin enhances survival of PC12 cells by activating Ca2+ channels via the cyclic-AMP-protein kinase A pathway, but that 6R-tetrahydrobiopterin does not preserve neuronal character induced by nerve growth factor.
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The hypothesis that prostaglandins contribute to hyperalgesia resulting from nerve injury was tested in rats in which the sciatic nerve was partially transected on one side. Subcutaneous injection of indomethacin (a classic inhibitor of cyclo-oxygenase) into the affected hindpaw relieved mechanical hyperalgesia for up to 10 days after injection. Subcutaneous injection of meloxicam or SC-58125 (selective inhibitors of cyclo-oxygenase-2) into the affected hindpaw also relieved mechanical hyperalgesia, but with a shorter time-course. ⋯ Comparable injections into the contralateral paw or abdomen had no effect on mechanical or thermal hyperalgesia, suggesting that the effects we observed were local rather than systemic. We conclude that prostaglandins, probably prostaglandin E1 or E2, contribute to the peripheral mechanisms underlying hyperalgesia following nerve injury. These data provide further evidence that inflammatory mediators contribute to neuropathic pain, and may warrant further study of peripherally administered non-steroidal anti-inflammatory drugs as a possible treatment for such pain in patients.
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Nociceptive-specific and multireceptive neurons in the lumbar dorsal horn are excited by noxious stimuli applied to the hindpaw and inhibited by noxious stimuli applied to distant body regions. Given that at least a subset of these neurons are part of the circuit for nociceptive reflexes, inhibition of nociceptive-specific and multireceptive neurons should inhibit nociceptive reflexes. Unfortunately, previous attempts to test this hypothesis have been inconclusive because of methodological differences between electrophysiological and behavioral experiments. ⋯ However, inhibition of nociceptive-specific and multireceptive neurons concomitant with a shift in the hindlimb reflex from flexion to extension suggests that these neurons are part of the circuit for flexor reflexes specifically. Presumably, lateral inhibition from the flexor to extensor circuit allows for the release of hindlimb extension when neurons in the flexion circuit are inhibited by a distant noxious stimulus. Such a system reduces the chance of injury by allowing for withdrawal reflexes to a single noxious stimulus and escape reactions, such as running and jumping, to multiple noxious stimuli.
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The immunocytochemical distribution of retinoid receptors has been analysed in the mouse adult central nervous system. All retinoic acid receptors (alpha, beta and gamma) and retinoid X receptors (alpha, beta and gamma) were detected and found to exhibit specific patterns of expression in various areas of the telencephalon, diencephalon and rhombencephalon. The protein localization of several retinoic acid receptors and retinoid X receptors did not correlate with the distribution of the corresponding RNA transcripts, as studied by in situ hybridization and RNase protection assays. This suggests that the expression of retinoid receptors could be post-transcriptionally regulated, which may contribute to their specific localization in the adult nervous system.
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The serotonin1A receptor partial agonist, buspirone, also displays antagonist properties at D2 receptors and is metabolized to the alpha2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine). Herein, we examined mechanisms underlying the influence of buspirone alone, and in association with the serotonin reuptake inhibitor, fluoxetine, upon extracellular levels of serotonin, dopamine and noradrenaline simultaneously quantified in the frontal cortex of freely moving rats. Buspirone (0.01-2.5 mg/kg, s.c.) dose-dependently decreased dialysate levels of serotonin (-50%), and increased those of dopamine (+100%) and noradrenaline (+140%). ⋯ The facilitatory influence of buspirone upon resting and fluoxetine-stimulated dopamine and noradrenaline levels may also involve its serotonin1A properties. However, its principal mechanism of action in this respect is probably the alpha2-adrenergic antagonist properties of its metabolite, 1-(2-pyrimidinyl-piperazine). The present observations are of significance to experimental and clinical studies of the influence of buspirone upon depressive states, alone and in association with antidepressant agents.